Aminoazole derivatives and their production and use

ABSTRACT

A compound of the formula: ##STR1## wherein A is the group of the formula: 
     
         Ar.sup.1 --D--Ar.sup.2 -- 
    
     wherein Ar 1  is a phenyl or thienyl group which may be optionally substituted with at least one of the same or different halogen atom; Ar 2  is a phenylene or thienylene group which may be optionally substituted with at least one of the same or different halogen atom; D is a divalent radical selected from the group consisting of &gt;C═N--OR 4  [wherein R 4  is a hydrogen atom or lower alkyl group], &gt;C═O, ##STR2## &gt;CHOH, &gt;NH radical, or single bond, ##STR3## wherein R 5  is a lower alkoxy or a phenyl group which may be optionally substituted with at least one of the same or different halogen atom; E is a methine group or a nitrogen atom; F is a vinylene group or an oxygen atom, ##STR4## wherein R 6  is a lower alkoxy group; R 7  is a lower alkyl group; R 8  is a benzoyl group which may be optionally substituted with at least one of the same or different halogen atom, B is a divalent azole group; R 1  is a hydrogen atom or a lower alkyl group; R 2  is a hydrogen atom, lower alkyl, aryl-lower alkyl, or the group of the formula: 
     
         R.sup.9 --G-- 
    
     wherein R 9  is a hydrogen atom, lower alkyl, halo-lower alkyl, amino-lower alkyl, aryl or aryl-lower alkyl group or the group of the formula: ##STR5## wherein R 10  is a hydrogen atom or lower alkoxy group; R 11  is a hydrogen atom, lower alkyl, lower alkenyl, lower cycloalkyl, aryl-lower alkyl, aryl or aroyl group; or the group of the formula: --NR 10  R 11  is a 5-, 6- or 7-membered saturated heterocyclic ring; or the group of the formula: 
     
         R.sup.12 --O-- 
    
     wherein R 12  is a lower alkyl or polyhalo-lower alkyl group; G is a divalent group selected from the group consisting of &gt;C═O, &gt;C═S, &gt;(C═O) 2  or &gt;SO 2  radical; or the group of the formula: --NR 1  R 2  is a 5-, 6- or 7-membered saturated heterocyclic ring: R 3  is a hydrogen atom or lower alkyl group, or its acid addition salts, which is useful for immunomodulator.

This invention related to novel aminoazole derivatives useful astherapeutic and preventive agents of autoimmune diseases, for example,rheumatoid arthritis or systemic lupus erythematodes, inflammatory,allergy and asthma, and their production and use. More particularly, thenovel compounds of this invention are those of the formula: ##STR6##wherein A is the group of the formula:

    Ar.sup.1 --D--Ar.sup.2

wherein Ar¹ is a phenyl or thienyl group which may be optionallysubstituted with at least one of the same or different halogen atom; Ar²is a phenylene or thienylene group which may be optionally substitutedwith at least one of the same or different halogen atom; D is a divalentradical selected from the group consisting of >C═N--OR⁴ [wherein R⁴ is ahydrogen atom or lower alkyl group], >C═O, ##STR7## >CHOH, >NH radical,or single bond, ##STR8## wherein R⁵ is a lower alkoxy or a phenyl groupwhich may be optionally substituted with at least one of the same ordifferent halogen atom; E is a methine group or a nitrogen atom; F is avinylene group or an oxygen atom, ##STR9## wherein R⁶ is a lower alkoxygroup; R⁷ is a lower alkyl group; R⁸ is a benzoyl group which may beoptionally substituted with at least one of the same or differenthalogen atom, B is a divalent azole group; R¹ is a hydrogen atom or alower alkyl group; R² is a hydrogen atom, lower alkyl, aryl-lower alkyl,or the group of the formula:

    R.sup.9 --G--

wherein R⁹ is a hydrogen atom, lower alkyl, halo-lower alkyl,amino-lower alkyl, aryl or aryl-lower alkyl group or the group of theformula: ##STR10## wherein R¹⁰ is a hydrogen atom or lower alkyl group;R¹¹ is a hydrogen atom, lower alkyl, lower alkenyl, lower cycloalkyl,aryl-lower alkyl, aryl or aroyl group, the group of the formula: --NR¹⁰R¹¹ is a 5-, 6-, 7-membered saturated heterocyclic ring, or the group ofthe formula:

    R.sup.12 --O--

wherein R¹² is a lower alkyl or polyhalo-lower alkyl group; G is adivalent group selected from the group consisting of >C═O, >C═S, >(C═O)₂or >SO₂ radical; or the group of the formula: --NR¹ R² is a 5-, 6- or7-membered saturated heterocyclic ring; and R³ is a hydrogen atom orlower alkyl group, and the pharmaceutically acceptable acid additionsalts thereof.

Various compounds, such as steroids, nonsteroidal anti-inflammatorydrugs and gold compounds, etc., are now widely use in treatment ofautoimmune diseases, for example, rheumatoid arthritis, but all of theirdrugs are limited use clinically because of their side effects inaddition to unreliable clinical effects. As a result of the elucidationsfor the pathogenesis of autoimmune diseases, immunomodulators, which mayalter the course of the diseases, have been used for the treatment ofthe diseases. As the immunomodulators, levamizole and D-penicillamineare described in the publications, Saishin Igaku, 35, 1392 (1980) andIgaku no Ayumi, 101, 216 (1977) respectively. However, they produceserious side effects, which cause a great problem in their clinical use.

It has been reported that aminoazoles have several biologicalactivities. In recent years, 2-aminothiazoles such as fanetizole,2-phenethylamino-4-phenylthiazole, (U.S. Pat. No. 4,307,106) andlotifazole, 4-phenyl-2-(2',2',2'-trichloroethoxycarboxamido)thiazole,(E.P. Pat. No. 1,727), which regulate immune responses, are reported.

In addition, 2-aminothiazole derivatives were described as gastricsecretion inhibitor (E.P. Pat. No. 177,463). It was reported that2-aminooxazole derivatives were effective for asthma (D.E. Pat. No.2,459,380). It was reported that 5-aminoisoxazole derivatives wereeffective for convulsion and acute inframmation (F.R. Pat. No.2,068,418). 3-Amino-1,2,4-oxadiazole derivatives were described ashypotensive drug (F.R. Pat. No. 2,439,192), and as carrageenin-edemainhibitor (D.E. Pat. No. 2,124,907).

It has been hoped that therapeutic agents of rheumatoid arsthritis areeffective for chronic inflammation and active as regulants of the immuneresponse in the body. Rat-adjuvant arthritis test is useful aspharmacological model to examine effects for chronic inflammation, andmice-Arthus reaction is useful as pharmacological model to examine theimmune regulant activity.

D-penicillamine is non-effective for adjuvant arthritis test and arthusreaction, moreover, has many severe side-effects. Levamizole iseffective for Arthus reaction, however, is non-effective for adjuvantarthritis test and has many severe side-effects. Fanetizole andlotifazole are effective for Arthus reaction, however, are non-effectivefor adjuvant arthritis test.

Accordingly, for the therapeutic agent of rheumatoid arthritis have beendesired the compounds which is effective for both of adjuvant arthritistest and Arthus reaction, and furthermore, have less side effect.

As the result of an extensive study, it has now been found that theaminoazole derivatives (I) of the invention exhibit depressiveactivities for both adjuvant arthrisis and Arthus reaction, in additionto inhibitory activity of 5-lipoxygenase. Therefore, the aminoazoles (I)are useful for treatment of autoimmune diseases, e.g. rheumatoidarthritis, systemic lupus erythematodes inflammatory, allergy, asthmae.t.c. This invention is based on the above finding.

Accordingly, a main object of the invention is to provide theaminoazoles (I) and their pharmaceutically acceptable acid additionsalts. Another object of this invention is to provide processes forproduction of the aminoazoles (I). A further object of the invention isto provide use of the aminoazoles (I) as immunomodulators oranti-inflammatory drugs.

In the compounds of the above formula (I) and elsewhere in thespecification, the terms "alkyl" and "alkenyl" means both straight andbranched-C₁₋₄ hydrocarbon chains, and the lower alkyl may be C₁₋₄ alkylsuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl. The lower alkenyl may be C₂₋₄ alkenyl such asvinyl, allyl, n-propenyl, isopropenyl, 2-methyl-1-propenyl, 1- or 2- or3-butenyl and the like. The lower alkoxy may be C₁₋₄ alkoxy such asmethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like. Thehalo-lower alkyl may be halo(C₁₋₄)alkyl such as chloromethyl,bromomethyl, 1-chloroethyl, 2-chloroethyl, 1-bromoethyl, 2-bromoethyl,1-chloropropyl, 2-chloropropyl, 3-chloropropyl and the like. Thepolyhalo-lower alkyl may be polyhalo(C₁₋₄)alkyl such as trifluoromethyl,trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl and thelike. The amino-lower alkyl may be amino(C₁₋₄)alkyl such as aminomethyl,2-aminoethyl, 3-aminopropyl, 2-(N-methylamino)ethyl,2-(N,N-dimethylamino)ethyl. The lower cycloalkyl may be C₃₋₆ alicyclicgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike. The aryl may be a phenyl group which may be optionally substitutedwith the lower alkyl group, such as phenyl, 4-methylphenyl,4-ethylphenyl and 4-isopropylphenyl and the like. The aryl-lower alkylmay be phenyl(C₁₋)alkyl such as benzyl, phenethyl, phenylpropyl. Thesubstituted benzoyl may be a benzoyl group substituted with at least oneof the same or different halogen atom, e.g., 4-chlorobenzoyl,4-fluorobenzoyl, 2-chlorobenzoyl, 2-fluorobenzoyl. The aroyl may bebenzoyl or benzoyl group substituted with at least one of the same ordifferent halogen atom, or of the same or different lower alkyl group,e.g. 4-chlorobenzoyl, 4-fluorobenzoyl, 4-methylbenzoyl. The term"halogen" includes, fluorine, chlorine, bromine and iodine. The 5-, 6-,7-membered saturated heterocyclic ring may, for example, bepyrrolidinyl, piperidinyl, hexahydroazepinyl. The azole group is a5-membered heterocyclic ring having one nitrogen atom and further atleast one selected from the group consisting of oxygen, sulfur andnitrogen atom, such as, thiazole, oxazole, isoxazole, oxadiazole,isothiazole, thiadiazole, pyrazole, imidazole, triazole and the like.

Among the amino azole compounds (I) of the invention, those of thefollowing formula are preferable: ##STR11## wherein Ar³ is a phenylgroup which may be optionally substituted with at least one of the sameor different halogen atom; Ar⁴ is a phenylene group which may beoptionally substitued with at least one of the same or different halogenatom; D¹ is carbonyl group or single bond; B¹ is the divalent azolegroup of thiazolediyl, oxazolediyl, isoxazolediyl or oxadiazolediyl; R¹³is lower alkyl group; R¹ and R² are as defined above and thepharmaceutically acceptable acid addition salts.

The compounds of the formula are more preferable: ##STR12## wherein X ishydrogen or halogen atom; B¹, R¹, R², R¹³ are as defined above and thepharmaceutically acceptable acid addition salts.

The compounds of the formula are most preferable: ##STR13## wherein R¹⁴is hydrogen atom or lower alkyl group; X, B¹, R¹, R² are as definedabove and the pharmaceutically acceptable acid addition salts.

The pharmaceutically acceptable acid addition salts of the novelaminoazole derivatives are also embraced by the present invention andare readily prepared by contacting the free base with the appropriatemineral or organic acid in either aqueous solution or in a suitableorganic solvent. The solid salt may then be obtained by precipitation orby evaporation of the solvent. The pharmaceutically acceptable acidaddition salts of this invention include, but are not limited to, thehydrochloride, hydrobromide, sulfate, phosphate, formate, acetate,fumarate, maleate, malate, tartrate, aspartate, glutamate,methanesulfonate, benzenesulfonate, p-toluenesulfonate,hydroxybenzenesulfonate, dihydroxybenzenesulfonate, and the like. Thecompounds of this invention include optical isomers, tautomers, all ofhydrates and those crystal forms.

The amino azole compounds (I) can be produced by various processes, ofwhich typical examples are set forth below.

Process (A):

The process of the azole (I) comprises cyclization:

The cyclization processes comprise the following five procedures:##STR14## wherein Y¹ is a leaving group such as halogen (e.g. chlorine,bromine), alkylsulfonyloxy (e.g. methanesulfonyloxy) or arylsulfonyloxy(e.g. p-toluenesulfonyloxy), and A, R¹, R² and R³ are as defined above.

The compound (IV) is obtained by reacting the compound (II) with thecompound (III) in an inert solvent at room temperature or under heating.As the solvent, there may be used water, alcohols (e.g. methanol,ethanol), ethers (e.g. ethyl ether or tetrahydrofuran), haloalkanes(e.g. dichloromethane, chloroform) or their mixture. ##STR15## wherein Aand R³ are as defined above.

The compound (VI) is obtained by reacting the compound (V) withcyanamide in an inert solvent at room temperature or under heating inthe presence of the base such as sodium hydroxide, potassium hydroxide,sodium carbonate or potassium carbonate. As the solvent, there may beused alcohols (e.g. methanol, ethanol), ethers (e.g. tetrahydrofuran,1,4-dioxane), water or their mixture. ##STR16## wherein A and R³ are asdefined above.

The compound (VIII) is obtained by reacting the compound (VII) withhydroxylamine in an inert solvent at room temperature or under heating.As the solvent, there may be used alcohols (e.g. methanol, ethanol),aromatic hydrocarbons (e.g. benzene, toluene), haloalkanes (e.g.dichloromethane, chloroform), ethers (e.g. tetrahydrofurane,1,4-dioxane), N,N-dimethylformamide, N,N-dimethylacetamide or pyridine.In case using hydroxylamine-acid salts, the reaction in presence of theacid binding agent may be effective. As the acid-binding agent, theremay be used an inorganic base or organic base, of which example aresodium hydroxide, potassium hydroxide, sodium carbonate, sodiumbicarbonate, triethylamine or pyridine. ##STR17## wherein A, R¹, R² andR³ are as defined above.

The compound (XI) is obtained by reacting the compound (IX) or itsreactive ester with the compound (X) in an inert solvent at roomtemperature or under heating. As the solvent, there may be used aromatichydrocarbons (e.g. benzene, toluene), haloalkanes (e.g. dichloromethane,chloroform), ethers (e.g. tetrahydrofuran, 1,4-dioxane),N,N-dimethylformamide, N,N-dimethylacetamide or pyridine. As thereactive ester of the compound (IX), there may be used a carboxylic acidhalide (e.g. chloride, bromide, iodide), carboxylic anhydride includinga mixed anhydride, a carboxylic azide or an active ester such as4-acyloxy-2,3-dihydro-2,5-diphenyl-3-oxothiophene-1,1-dioxide. The freeacid may be reacted in presence of N,N-dicyclohexylcarbodiimide(DCC),1-hydroxybenztriazole (HOBT)-DCC, N,N-carbonyldiimidazole or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(WSC.HCl).The acid chloride or anhydride may be preferably reacted in the presenceof the acid-binding agent (e.g. sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate, triethylamine or pyridine). Incase the intermediate (XII) is isolated in this reaction, it can beconverted to the compound (XI) via intermolecular cyclization followedby dehydration with further heating in the presence or absence of aninert solvent. ##STR18## wherein A and R³ are as defined above.

The compound (XIV) is obtained by reacting the compound (XIII) withhydroxylamine in an inert solvent at room temperature or under heating.As the solvent, there may be used aromatic hydrocarbons (e.g. benzene,toluene), ethers (e.g. tetrahydrofuran, 1,4-dioxane),N,N-dimethylformamide, N,N-dimethylacetamide or pyridine. In case usinghydroxylamine-acid salts, the reaction in presence of the acid bindingagent may be effective. As the acid-binding agent, there may be used aninorganic base or organic base, of which example are sodium hydroxide,potassium hydroxide, sodium carbonate, sodium bicarbonate, triethylamineor pyridine. ##STR19## wherein Y² is a leaving group such as halogen(e.g. chlorine, bromine), alkylsulfonyloxy (e.g. methanesulfonyloxy) orarylsulfonyloxy (e.g. p-toluenesulfonyloxy), and A, B, G, R¹, R³ and R⁹are as defined above.

The compound (XVII) is obtained by reacting the compound (XV) with thecompound (XVI) in an inert solvent in the presence of acid-binding agentat the condition from ice-cooling to heating. As the solvent, there maybe used aromatic hydrocarbons (e.g. benzene, toluene), haloalkanes (e.g.dichloromethane, chloroform), ethers (e.g. tetrahydrofuran,1,4-dioxane), N,N-dimethylformamide, N,N-dimethylacetamide or acetone.As the acid-binding agent, there may be used an inorganic base ororganic base, of which example are sodium hydroxide, potassiumhydroxide, sodium carbonate, sodium bicarbonate, triethylamine orpyridine. In case the reaction is performed under two-phase condition,use of phase-transfer catalysis may be effective. ##STR20## wherein R¹⁵is lower alkyl, aryl-lower alkyl or aryl and A, R¹ and R³ are as definedabove.

The compound (XIX) is obtained by reducing the compound (XVIII) withmetal hydride such as lithium aluminium hydride at a temperature fromcooling to under heating. As the solvent, there may be used ethyl ethers(e.g. ether tetrahydrofuran). ##STR21## wherein R¹⁶ is lower alkyl oraryl-lower alkyl; Y³ is a leaving group such as halogen (e.g. chlorine,bromine), alkylsulfonyloxy (e.g. methanesulfonyloxy) or arylsulfonyloxy(e.g. p-toluenesulfonyloxy) and, A, B and R³ are as defined above.

The compound (XXII) is obtained by reacting the compound (XX) with thecompound (XXI) in an inert solvent at a temperature from cooling toheating. As the solvent, there may be preferably used solvents combinedhydrophobic solvent such as benezene or toluene with aqueous solution ofstrong base. Preferably this reaction is performed at room temperature.As the base, there may be used sodium hydroxide, potassium hydroxide orpotassium carbonate. ##STR22## wherein R¹⁷ is hydrogen or lower alkyl,R¹⁸ is a lower alkyl and A, B, R¹ and R³ are as defined above.

The compound (XXIV) is obtained by reacting the compound (XV) with thecompound (XXIII) under heating and then reducing with sodium borohydridein an inert solvent. As the solvent, there may be used alcohols (e.g.ethanol, propanol, isopropanol) or ethers (e.g. ethyl ether,tetrahydrofuran, 1,4-dioxane). ##STR23## wherein Ar¹, Ar², B, R¹, R² andR³ are as defined above.

The compound (XXVI) is obtained by treating of the compound (XXV) withethyleneglycol under the usual manner (for example "Shin-JikkenkagakuKouza" 14, (V), p. 2518, edited by NIHON-KAGAKUKAI). For example, thecompound (XXVI) is obtained by heating the compound (XXV) withethyleneglycol in aromatic hydrocarbons (e.g. benzene, toluene) inpresence of p-toluenesulfonic acid. ##STR24## wherein R¹⁹ is a hydrogenatom or lower alkyl and Ar¹, Ar², B, R¹, R² and R³ are as defined above.

The compound (XXVIII) is obtained by reacting the compound (XXV) withthe compound (XXVII) in an inert solvent at room temperature or underheating. As the solvent, there may be used alcohols (e.g. methanol,ethanol, propanol, isopropanol), ethers (e.g. tetrahydrofuran,1,4-dioxane), aromatic hydrocarbons (e.g. benzene, toluene), pyridine orwater. This reaction is performed by using of hydroxylamine-acid saltswith an acid-binding agent such as sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate,triethylamine or pyridine. ##STR25## wherein Ar¹, Ar², B, R¹, R² and R³are as defined above.

The compound (XXIX) is obtained by reducing the compound (XXV) withreducing agents such as sodium borohydride in an inert solvent at atemperature from ice-cooling to heating. As the solvent, there may beused alcohols (e.g. ethanol, n-propanol, isopropanol) or ethers (e.g.tetrahydrofuran, ethyl ether, 1,4-dioxane). ##STR26## wherein R²⁰ islower alkyl, and A, B and R³ are as defined above.

The compound (XXXI) is obtained by reacting the compound (XX) with thecompound (XXX) under heating, followed by hydrolyzing under acidcatalyst in an inert solvent. As the solvent, there may be used alcohols(e.g. methanol, ethanol, n-propanol, isopropanol), aromatic hydrocarbons(e.g. benzene, toluene), aliphatic hydrocarbons (e.g. hexane, heptane),haloalkanes (e.g. dichlorometane, chloroform), ethyl ether or theirmixture. As the acid catalyst, there may be used mineral acid (e.g.hydrochloric acid, sulfuric acid) or silica-gel. ##STR27## wherein Ar¹,Ar², B, R¹, R² and R³ are as defined above.

The compound (XXV) is obtained by hydrolysis of the compound (XXVI) byusual manner (for example, Sin-Jikkenkagaku-Kooza 14, (V), p. 2519,edited by NIHON-KAGAKUKI). For example, the compound (XXV) is obtainedby reacting the compound (XXVI) with 80% acetic acid at roomtemperature. ##STR28## wherein Q is oxygen or sulfer atom, R²¹ is loweralkyl, lower alkenyl, lower cycloalkyl, aryl-lower alkyl, aryl or aroylgroup, and A, B, R¹ and R³ are as defined above.

The compound (XXXIII) is obtained by reacting the compound (XV) with thecompound (XXXII) in an inert solvent at a temperature or underice-cooling or heating. As the solvent, there may be used alcohols (e.g.methanol, ethanol), aromatic hydrocarbons (e.g. benzene, toluene),ethers (e.g. tetrahydrofuran, 1,4-dioxane), haloalkane (e.g.dichloromethane, chloroform), N,N-dimethylformamide,N,N-dimethylacetamide or acetone. This reaction is preferably performedin presence of an inorganic base (e.g. sodium carbonate, potassiumcarbonate, sodium bicarbonate). If necessary, this reaction is performedafter the amines (XV) was converted to metal amide with metalating agentsuch as lithum diisopropylamide. ##STR29## wherein A, B, R¹ and R³ areas defined above.

The compound (XXXV) is obtained by hydrolysis of the compound (XXXIV) inan inert solvent in presence of base under heating. As the solvent,there may be use alcohols (e.g. methanol, ethanol), ethers (e.g.tetrahydrofuran, 1,4-dioxane), acetone, water or their mixture. As thebase, there may be used sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium bicarbonate. ##STR30## whereinR²² is halogen atom (e.g. chlorine, bromine) or lower alkyl group; R²³is a hydrogen atom, lower alkyl group or --NR₂ ²³ is a 5-, 6-,7-membered saturated heterocyclic ring, and A, B, R¹ and R³ are asdefined above.

The compound (XXXVIII) is obtained by reacting the compound (XXXVI) withthe compound (XXXVII) in an inert solvent under heating. As the solvent,there may be used aromatic hydrocarbons (e.g. benzene, toluene), ethers(e.g. tetrahydrofuran, 1,4-dioxane), haloalkanes (e.g. dichloromethane,chloroform) or pyridine. ##STR31## wherein Z is halogen (e.g. chlorine,bromine, iodine), R²⁴ is a hydrogen atom and lower alkyl, n is integerfrom 1 to 4, and A, B, R¹ and R³ are as defined above.

The compound (XLI) is obtained by reacting the compound (XXXIX) with thecompound (XL) in an inert solvent. As the solvent, there may be usedaromatic hydrocarbons (e.g. benzene, toluene), ethers (e.g.tetrahydrofuran, 1,4-dioxane), haloalkanes (e.g. dichloromethane,chloroform), N,N-dimethylformamide, N,N-dimethylacetamide or pyridine.This reaction is effectively performed in the presence of an inorganicor an organic base (e.g. sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, sodium bicarbonate, triethylamine orpyridine) at a temperature from ice-cooling or to heating. ##STR32##wherein R²⁵ is lower alkyl or aryl-lower alkyl; Y⁴ is a leaving groupsuch as halogen (e.g. chlorine, bromine), alkylsulfonyloxy (e.g.methanesulfonyloxy) or arylsulfonyloxy (e.g. p-toluenesulfonyloxy), andA, B, R¹ and R³ are as defined above.

The compound (XLIII) is obtained by reacting the compound (XV) with thecompound (XLII) in an inert solvent in presence of the phase-transfercatalyst in addition to base. As the solvent, there may be used themixture of hydrophobic solvents (e.g. benzene, toluene) and water. Asthe base, there may be used sodium hydroxide, potassium hydroxide orpotassium carbonate.

The starting compounds (XV), (XVIII), (XX), (XXV), (XXXIV), and (XXXIX)are objective compounds of this invention and obtained by process (A-1),(A-2), (A-3), (A-4), (A-5), (B), (C), (E), (F), (J), (K) and (P). Andthe compounds (II), (III), (V), (VII), (IX), (X), (XIII), (XVI), (XXI),(XXIII), (XXVII), (XXX), (XXXII), (XXXVII) and (XLI) are known orobtained by usual manner. For example, the compound (II) and (V) areprepared by following process. ##STR33## wherein A, Y¹, and R³ are asdefined above.

The compound (V) is prepared by reacting the acid chloride of thecompound (IX) with tris(trimethylsilyloxy) ethylene according to theprocedure reported in literature (for example, A. Wissner, J. Org. Chem.44, (25) 4617 (1979)). The compound (II) is prepared from the compound(V) by the usual manner. For example, the compound (II) (wherein Y¹ ischlorine) is obtained by substitution of hydroxy group to chlorine atomwith triphenylphosphinecarbon tetrachloride system.

The compound (XII) is prepared by the following procedure. ##STR34##wherein R²⁶ is lower alkyl and A and R³ are as defined above.

The compound (XLIV) is obtained by esterification of the compound (IX)by usual manner and the compound (VII) is obtained by base-catalyticcondensation of the compound (XLIV) with acetonitrile.

The compound (XIII) is prepared by reacting the compound (IX) withcyanamide in an inert solvent at room temperature or under heatingaccording to the procedure reported in D.E. Pat. No. 2,843,887.##STR35##

The starting compound (X) is known or obtained by following process.##STR36## wherein R¹ and R² are as defined above.

The compound (XLVI) is obtained by dehydrating the compound (XLV)according to procedure reported in literature (for example, W. Schrothet al, Journal f. prakt, chemie, Band 325, Heft5, 1983, s 787-802).

The compound (X) is obtained by reacting the compound (XLVI) withhydroxylamine according to the procedure reported in literature(BETZECKI et al, Bull, Acad. Pol. Sci. Ser Sci, Chem., vol 18, No 8,431(1970)).

The compound (XXXVI) is obtained by following process; when R²² is ahalogen atom, the compound (XLVII) is prepared by reacting the compound(XV) with the compound (XLVII) in inert solvent at room temperature orunder heating. ##STR37## wherein Y⁵ is a halogen atom (e.g. chlorine,bromine), and A, B, R¹ and R³ are as defined above. When R²² is loweralkoxy group, the compound (XXXVI) is obtained by process (B).

As stated above, the aminoazoles (I) of this invention exertpharmaceutical activities to autoimmune diseases especially. The factsare well evidenced by the pharmacological test data as set forth below.

Test Method: [Rat-Adjuvant Arthritis Test]

Rat adjuvant arthritis test is one of a few and most usefulpharmacological model for the investigation of human clonicinflammation. It is known that the effective compounds to this modelsystem are useful for treatment of rheumatoid arthritis, such assteroids or non-steroidal anti-inflammatory drugs (Oyo Yakuri, 5, 169(1971).

According to the method of Winter et al., Arth. Rheum., 9, 394 (1966),male Sprague-Dawley rats, 6 weeks of age, were given subplantarinjection of the adjuvant consisting of 1 mg of killed Mycobacteriumbutyricum (Difco) and 0.2 ml of liquid paraffin. Fourteen days after,the rats with established arthritis were treated by the drug as follows:the test compound was suspended in 5% gum arabic solution and orallygiven once a day for 5 days, day 15 to day 19. Control rats were givengum arabic in the same way. On day 19, the volume of right foot wasdetermined with a plethusometer. The lowest dose which gave significantreduction (p <0.001) of the foot volume from that of the control groupwas regarded as a minimum effective dose (MED).

[Mice-Arthus Test]

It's thought that rheumatoid arthritis is a disease with disorder ofimmunity and one of origins of this disease is Arthus reaction inducedby immune complex (Ivan M. Roitt, 1980, "Essential Immunology"). Theactivity of effect for rheumatoid arthritis may be estimated by effectfor Arthus reaction.

According to the method of Abe et al., Enshou, 1, 739 (1981), maleBABL/c mice, 6 weeks of age, were sensitized by injection of 8×10⁷ sheepred blood cells (SRBC) (Nihon Bio-Sap. Center) in 0.2 ml of phosphatebuffered saline (PBS) into the tail vein. Two weeks later, mice wereboosted by the i.v. injection of 8×10⁷ SRBC and 5 day later the animalswere challenged by the subcutaneous injection of 1×10⁸ SRBC in 25 μl ofPBS into the right hind footpad. The thickness of the SRBC-injectionright hind paw and contralateral left hind paw were measured withmicrometer 3 hr after the challenge. The difference between these twomeasurements is regarded as the oedema due to the Arthus reaction.Percentage inhibition of the reaction was determined by comparison withthe positive control group. The test compounds were administered orally24 hr and 1 hr before the challenge. Results of two tests for compoundsof example 2, 7, 9, 11, 21, 22, 48, 67, 74 are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________    Results of Rat-Adjuvant Arthrits Test and                                     Mice-Arthus Test                                                                                                Minimum Effective Dose                      Example                           (mg/kg)                                     No.  Structure                    Adjuvant Arthritis                                                                      Arthus                            __________________________________________________________________________          ##STR38##                   25        10                                7                                                                                   ##STR39##                   10        10                                9                                                                                   ##STR40##                   10        50                                11                                                                                  ##STR41##                   2.5       10                                21                                                                                  ##STR42##                   2.5       10                                22                                                                                  ##STR43##                   2.5       50                                48                                                                                  ##STR44##                   10        50                                67                                                                                  ##STR45##                   10        50                                74                                                                                  ##STR46##                   2.5       50                                     levamizole                   non-effective                                                                           50                                                                  at 50 mg/kg                                      D-Penicillamine              non-effective                                                                           non-effective                                                       at 200 mg/kg                                                                            at 50 mg/kg                       __________________________________________________________________________

The compounds of this invention are effective for both rat adjuvantarthritis test and mice Arthus reaction test, on the other hand,levamizole is non-effective for rat adjuvant arthritis andD-penicillamine is non-effective for both rat adjuvant arthritis andmice Arthus reaction. Therefore, the compounds of this invention areuseful therapeutic agents of rheumatoid arthritis. That is to say, it ischaracteristic in that the compounds of this invention are effective forthe treatment of not only rheumatoid arthritis but also disorder ofimmunity.

In addition, the compounds of this invention are effective to improveseveral immunological factors of spontaneous autoimmune disease animal:MRL/1 mice. The results obtained suggest a potential role for thecompounds of this invention in the treatment of autoimmune disease inhuman, e.g., rheumatoid arthritis.

Additionally, the compounds of this invention are effective as5-lipoxygenase inhibitor as set forth below.

Test Method: [5-Lypoxygenase Inhibitory Test]

According to the method of Harvey et al., J. Pharmacol. Meth., 9,147-155 (1983), polymorphonuclear leukocytes (PMNs) from Hartley guineapigs weighting 280 to 350 g were elicited by intraperit oneal injectionof 2% casein suspension (10 ml/100 g guiner pig weight), and collected16-18 hrs later. The cells were washed with saline and finally suspendedat 2.39×10⁷ cells/ml in Krebs Ringer Bicarbonate buffer (KBR) pH 7.4.

935 μl of PMNs were aliquoted into 15 ml glass tubes and prewarmed to37° C. in a shaking water bath. Drugs (10 μl of dimethylsulfoxide (DMSO)were added 10 minutes prior to the addition of 1-¹⁴ C-arachidonic acid(New England Neuclear Co.; 50 μl of 2 μCi/mlKBR) and calciumionophor,A23187 (Calbiochem Boehring Co.; 5 μl of 1 mg/mlDMSO). The reaction wasterminated after a further 10 min by the addition of 0.2M citric acid(100 μl). Unstimulated controls were also included to determine theincreased metabolism of arachidonic acid due to A23187. Samples werediluted with water (4 ml) and extracted twice with ethyl acetate (5 ml).The ethyl acetate was concentrated under a stream of nitrogen andtwo-thirds of the residue was applied to TLC plates. The plates weredeveloped in toluene: dioxane: acetic acid=65:34:1.5 at 10° C.

Radiochromatographic analysis of the labelled metabolites of [¹⁴ C]arachidonic acid utilised a Berthold LB283 TLC Linear Analyzer. Insamples and controls, a ratio of radioactivity of 5-HETE in metabolitesto all of metabolites of [¹⁴ C] arachidonic acid was calculated, andresults were determined as present inhibition calculated from thoseretios. ##EQU1##

Results of 5-lipoxygenase inhibition for compounds of example 21, 22, 65and 67 are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Results of 5-Lipoxygenase Inhibitory Test                                     Example No.   Activity of Inhibition                                          ______________________________________                                        21            ++                                                              22            +++                                                             65            +++                                                             67            +++                                                             ______________________________________                                    

From the above results, the compounds of this invention possess5-lipoxygenase inhibitory activity and, therefore, they may be usefulfor treatment of allergy and inflammation, e.g., allergic asthma andallergic rhinitis.

The compounds (I) of present invention may be used in the form ofpharmaceutical composition adapted for enteral or parenteraladministration. Accordingly, by conventional routes, for oraladministration the compounds may be combined with a suitable solid orliquid carrier or diluent to form tablets, capsules, powders, syrups,solutions, suspensions and the like. For parenternal administration thecompounds may be combined with sterile aqueous or organic media to forminjectable solutions or suspensions. The compounds may be administeredto rectum as suppositories.

In man, the compounds of this invention may generally be administered inan amount of from about 5 mg/day to 2000 mg/day, perferably about 25mg/day to 1000 mg/day, depending upon the symptom, the route ofadministration, and the particular compounds of the invention.

The present invention is illustrated by the following examples. However,it should be understood that the invention is not limited to thespecific details of these examples.

REFERENCE EXAMPLE 1 ##STR47##

In usual manner, lithium diisopropylamide in tetrahydrofuran wasprepared with diisopropylamine (3.2 ml, 22.6 mmol) and 1.6Mn-butyllithium in hexane (14.2 ml, 22.6 mmol). ("Reagents for OrganicSynthesis", 2, p. 249) To this lithium diisopropylamide intetrahydrofuran was added dropwise 4-biphenylyl acetic acid (2.40 g,11.3 mmol) in tetrahydrofuran at from -50° C. to -30° C. After themixture was reacted at from -40° C. to -10° C. for 2 h, to the mixturewas added dropwise methyliodide (1.77 g, 12.4 mmol) in tetrahydrofuran,then the temperature was rised at from -30° C. to room temperature innature. After the mixture was stirred for 4 h, was added water and wasadjusted at pH 2 with 3N sulfonic acid, then extracted with ether. Afterthe ether extract was dried over, then the extract was evaporated underreduced pressure to a residue, which was chromatographed to afford2-(4-biphenylyl)propionic acid (2.38 g, 93% yield) as white crystallinematerial: mp 144°-145° C.

REFERENCE EXAMPLE 2 ##STR48##

To thionyl chloride (40 ml) was added 2-(2-fluoro-4-biphenylyl)propionic acid (10.0 g, 40.9 mmol) by portions with stirring at roomtemperature. After the addition, the mixture was stirred over night atroom temperature, and the solution was evaporated under reduced pressureto afford the acid chloride. After tris(trimethylsilyloxy)ethylene (35.9g, 123 mmol) was added to the acid chloride at room temperature, themixture was stirred at 95° C. for 4 h, then cooled to room temperature.After the addition of dioxane (53.3 ml) and then 0.6N hydrochloric acid(21.5 ml) dropwise to the mixture, the solution was stirred at 85° C.for 30 min, then cooled to room temperature, saturated with sodiumchloride, and extracted with ether. The ether extracts were washed withwater, dried with anhydrous sodium sulfate, and evaporated under reducedpressure to a residue, which was chromatographed to afford3-(2-fluoro-4-biphenylyl)-2-oxo-1-butanol (10.0 g, 95% yield) ascrystalline material: mp 63°-64.5° C. NMR(CDCl₃)δ 1.48(d, 3H), 2.97(t,1H), 3.80(q, 1H), 4.25(d, 2H), 6.93-7.62(m, 8H) ppm; IR(neat) 3450,1725, 1610, 1480, 1420, 1270 cm³¹ 1.

According to substantially the same procedure as that of ReferenceExample 2, the following compounds were made.

                                      TABLE 3                                     __________________________________________________________________________    Ref. Ex. No.                                                                         Structure                Physical Data                                 __________________________________________________________________________            ##STR49##               mp. 87.5˜89.0° C.                4                                                                                     ##STR50##               NMR(CDCl.sub.3) δ 1.49(d,3H)                                            2.97(t,1H), 3.85(q,1H), 4.20(d,2H),                                           7.22-7.82 (m,9H) ppm; IR(neat) 3480,                                          1720, 1660, 1600, 1320, 1280                  __________________________________________________________________________                                    cm.sup.-1                                 

REFERENCE EXAMPLE 5 ##STR51##

To 3-(2-fluoro-4-biphenylyl)-2-oxo-1-butanol (2.00 g, 7.74 mmol) incarbon tetrachloride (5 ml) was added triphenylphosphine (2.15 g, 8.20mmol) at room temperature. After the addition, the mixture was stirredover night at room temperature, then concentrated to givetriphenylphosphine oxide as precipitates. After filtration of theprecipitates, the filtrates were evaporated under reduced pressure to aresidue, which was chromatographed to afford1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (1.01 g, 47% yield) ascrystalline materials: mp 57°-59° C.; NMR(CDCl₃)δ 1.48(d, 3H), 4.07(m,3H), 6.93-7.63(m, 8H); IR(neat) 1740, 1620, 1480, 1420, 1270 cm⁻¹.

According to substantially the same procedure as that of ReferenceExample 5, the following compounds were made.

                                      TABLE 4                                     __________________________________________________________________________    Ref. Ex. No.                                                                         Structure              Physical Data                                   __________________________________________________________________________            ##STR52##             mp. 101.0˜102.5° C.                7                                                                                     ##STR53##             NHR(CDCl.sub.3) δ 1.54(d,3H),                                           4.06(s,2H), 4.13(q,1H), 7.30˜7.90(m,9H                                  )ppm; IR(neat) 1735, 1660, 1600, 1320, 1280                                   cm.sup.-1                                       __________________________________________________________________________

REFERENCE EXAMPLE 8 ##STR54##

To 2-(2-fluoro-4-biphenylyl)-propionic acid (30.0 g, 0.123 mol) inethanol (300 ml) was added conc. sulfonic acid (3.0 g). After theaddition, the mixture was stirring at 50° C. for 5 h, the concentratedand extracted with benzene. The benzene extracts were washed withaqueous sodium hydrogen carbonate solution then with water, and driedover. The extracts were evaporated under reduced pressure to affordethyl-2-(2-fluoro-4-biphenylyl)propionate (33.6 g, 0.123 mol) as oilyresidue.

After 60% sodium hydride (6.5 g, 0.163 mmol) was suspended intetrahydrofuran under nitrogen atmosphere, the mixture was refluxed for0.5 h, then added dropwise acetonitrile (7.6 g, 0.185 mol) andethyl-2-(2-fluoro-4-biphenylyl)-propionate described above intetrahydrofuran (100 ml). After refluxed for 2 h, the mixture was cooledat room temperature and added isopropylalcohol. After stirring for awhile, the mixture was evaporated under reduced pressure to a residue,which was made acid with 2N hydrochloric acid and extracted withchloroform. The extracts were washed with water, dried over, andevaporated under reduced pressure to a residue, which waschromatographed and recrystallized with ethanol to afford4-(2-fluoro-4-biphenylyl)-3-oxo-pentanenitril (18.0 g, 55% yiled) aspale yellow crystalline material: mp 84°-85° C.

According to substantially the same procedure as that of ReferenceExample 8, the following compound was made.

                  TABLE 5                                                         ______________________________________                                        Ref.                                                                          Ex.                                                                           No.  Structure          Physical Data                                         ______________________________________                                              ##STR55##         NMR(CDCl.sub.3) δ 3,16(s,2H), 3.91(s,2H),                               7.25˜7.66 (m,9H) ppm; IR(neat) 2260, 1730,                              1380, 1350, 1120 cm.sup.-1                            ______________________________________                                    

REFERENCE EXAMPLE 10 ##STR56##

According to substantially the same procedure as that of ReferenceExample 8, ethyl 2-(3-benzoylphenyl) propionate (quantitative yield) wasobtained from 2-(3-benzoylphenyl) propionic acid (30 g, 0.118 mol).

To ethyl 2-(3-benzoylphenyl) propionate in toluene (200 ml), was addedethylene glycol (20.0 g) and p-toluenesulfonic acid monohydrate (1.0 g).After refluxed for 13 h, the mixture was cooled at room temperature andextracted with benzene. The extracts were washed with aqueous sodiumhydrogen carbonate solution and then with water, and evaporated underreduced pressure to a residue, which was chromatographed to afford ethyl2-(3-(2-phenyl-1,3-dioxolan-2-yl)phenyl) propionate (29.0 g, 75% yield)as oily residue: NMR(CDCl₃)δ 1.15(t, 3H), 1.47(d, 3H), 3.68(q, 2H),4.02(s, 4H), 4.07(q, 1H), 7.16-7.85(m, 9H) ppm; IR(neat) 3050, 1740,1605, 1180, 1080 cm⁻¹.

REFERENCE EXAMPLE 11 ##STR57##

According to substantially the same procedure as that of ReferenceExample 8, with ethyl 2-(3-(2-phenyl-1,3-dioxolan-2-yl)phenyl)propionate(38.5 g, 118 mmol) was obtained4-(3-(2-phenyl-1,3-dioxolan-2-yl)-phenyl)-3-oxo-pentanenitrile (12.1 g,32% yield) as pale yellow oily substance: NMR(CDCl₃)δ 1.41(d, 3H),3.28(s, 2H), 3.85(q, 1H), 4.03(s, 4H), 7.00-7.60(m, 9H) ppm; IR(neat)2900, 2250, 1730, 1600, 1170, 1080 cm⁻¹.

REFERENCE EXAMPLE 12 ##STR58##

To N-methylbenzylamine (12.1 g, 0.1 mol) was added urea (6.0 g, 0.1mol). After stirred at 118° C. for 4 h, the mixture was cooled to roomtemperature. The solidified mixture was ground to a powder, washed withn-hexane and recrystallized with ethyl acetate to affordN-methyl-N-benzylurea (12.3 g, 75% yield): mp 125°-129° C.

To N-methyl-N-benzylurea (1.64 g, 0.01 mol) in chloroform (24 ml) and50% aqueous sodium hydroxide solution (5.4 ml) was added triethylamine(0.1 g, 0.001 mol) and the mixture was vigorously stirred at roomtemperature for 3.5 h. After addition of water and chloroform, themixture was stirred, then extracted with chloroform. The extracts werewashed with water, dried with anhydrous sodium sulfate, and evaporatedunder reduced pressure to a residue, which was chromatographed to affordN-methyl-N-benzylcyanamide (1.2 g, 82% yield) as oily substance:NMR(CDCl₃)δ 2.77(s, 3H), 4.14(s, 2H), 7.25-7.50(m, 5H); IR(neat) 2220,1495, 1455, 1365, 730 cm⁻¹.

According to substantially the same prosedure as that of ReferenceExample 12, the following compound was made.

                  TABLE 6                                                         ______________________________________                                        Ref. Ex. No.                                                                           Structure     Physical Data                                          ______________________________________                                        13                                                                                      ##STR59##    b.p. 80˜84° C./10 mmHg; NMR(CDCl.sub.3                           ) δ 1.91(t, 4H), 3.39(t,4H),ppm; IR(neat)                               2200, 1455, 1350 cm.sup.-1                             ______________________________________                                    

REFERENCE EXAMPLE 14 ##STR60##

To N-methyl-N-benzylcyanamide (10.6 g, 7.3 mmol) in ethanol (10 ml) wasadded hydroxylamine (0.528 g, 7.3 mmol). After reflux with stirring for8 h, the mixture was evaporated under reduced pressure to a residue,which was recrystallized with mixture solution of iospropylalcohol andiospropylether to afford 1-methyl-1-benzyl-2-hydroxyguanidinehydrochloride (1.02 g, 65% yield) as crystalline material: mp 111°-114°C.

According to substantially the same procedure as that of ReferenceExample 14, the following compound was made.

                  TABLE 7                                                         ______________________________________                                        Ref. Ex. No.                                                                            Structure         Physical Data                                     ______________________________________                                        15                                                                                       ##STR61##        mp. 220° C. (decomposition)                ______________________________________                                    

REFERENCE EXAMPLE 16 ##STR62##

(+)-2-(2-Fluoro-4-biphenylyl)propionic acid (94.9% ee) was obtained bymethod of patent (Japan Kokai 53-112841). A solution of diazoketone inether which was obtained by reaction of(+)-2-(2-fluoro-4-biphenylyl)propionic acid (200 mg, 0.82 mmol) obtainedabove with diazomethane by usual manner [W. E. Bachmann, W. S. Struve,Org. React., 1, 38 (1942)] was bubbled hydrogen chloride gas for 5minute. The reaction mixture was washed with NaHCO₃ aq. and dried withmagnesium sulfate. After evaporation, the residue was chromatographed toafford (+)-1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (71.5 mg, 75%yield): (α)_(D) ²⁵° C. +180° (c=0.744, CHCl₃)

EXAMPLE 1 ##STR63##

To thiourea (1.77 g, 23.3 mmol) in water (50 ml) was added1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (5.25 g, 19.0 mmol). Afteraddition, the mixture was heated for 3 hr, and the solution was cooledto room temperature, then added IN sodium hydroxide to pH 8. The mixturewas extracted with chloroform and the chloroform extracts were washedwith water, dried over, and evaporated under reduced pressure to aresidue, which was chromatographed to afford2-amino-4-[1-(2-fluoro-4-biphenylyl)ethyl] thiazole (4.12 g, 73% yield)as crystalline material: mp 167°-168° C.

EXAMPLE 2 ##STR64##

To N-methylthiourea (5.55 g, 61.6 mmol) in water was heated with1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (16.50 g, 59.6 mmol) at90° C. for 3 hr. Treatment in same manner of Example 1 to give4-[1-(2-fluoro-4-biphenylyl)ethyl]-2-methylaminothiazole (13.15 g, 71%yield): mp 129°-129.5° C.

According to substantially the same procedure as that of Example 1,there were obtained the thiazole derivatives of the formular (IV) aslisted in Table 8.

                                      TABLE 8                                     __________________________________________________________________________    Example                                                                            Structure                    Physical Data                               __________________________________________________________________________          ##STR65##                   123.0-124.5° C.                      4                                                                                   ##STR66##                   136-137° C.                          5                                                                                   ##STR67##                   121-122° C.                          6                                                                                   ##STR68##                   163.0° C.                            __________________________________________________________________________

EXAMPLE 7 ##STR69##

To 3-(2-Fluoro-4-biphenylyl)-2-oxo-1-butanol (3.57 g, 13.8 mmol) intetrahydrofuran (35 ml) was added cyanamide (3.65 g, 77.6 mmol) in waterand 2N-sodium hydroxide to pH 10. After the addition, the mixture wasstirred overnight, then cyanamide (3.65 g, 77.6 mmol) was added to thereaction mixture to pH 10, the mixture was stirred overnight. Thereaction mixture was extracted with ether and the extracts were washedwith water, dried over and evaporated under reduced pressure to aresidue, which was chromatographed to afford2-Amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)oxazole as crystallinematerial (1.05 g, 27% yield): mp 150.5-151.5° C.

EXAMPLE 8 ##STR70##

To 4-(2-Fluoro-4-biphenylyl)-3-oxo-pentanenitrile (2.75 g, 10.3 mmol) inethanol (70 ml) was added hydroxylamine hydrochloride (1.1 g, 15.8 mmol)in pyridine (10 ml). After addition, the mixture was stirred at roomtemperature overnight, then evaporated under reduced pressure to aresidue, which was chromatographed and then recrystalyzed to afford5-amino-3-(1-(2-fluoro-4-biphenylyl)ethyl)isoxazole (2.20 g, 76% yield)as crystalline material: mp 122°-123° C.

According to substantially the same procedure as that of Example 8,there were obtained the isoxazole derivatives of the formula (VIII) aslisted in Table 9.

                                      TABLE 9                                     __________________________________________________________________________    Example                                                                            Structure                  Physical Data                                 __________________________________________________________________________          ##STR71##                 138.5-139.0° C.                        10                                                                                  ##STR72##                 145.5-146.0° C.                        __________________________________________________________________________

EXAMPLE 11 ##STR73##

To the mixture of 2-(3-benzoylphenyl) propionic acid (3.00 g, 11.8mmol), 1,1-dimethylamino-2-hydroxyguanidine hydrochloride (1.98 g, 14.2mmol), N-hydroxybenztriazole (1.91 g, 14.2 mmol) anddicyclohexylcarbodiimide (2.92 g, 14.2 mmol) in N,N-dimethylformamide(100 ml) were added triethylamine (1.43 g, 14.2 mmol). After theaddition, the mixture was stirred at room temperature for 12 hr, thenfilterated. The filterates were evaporated under reduced pressure to aresidue, which was chlomatographed to afford3-dimethylamino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (2.00 g,53% yield); NMR(CDCl₃)δ 1.27(d, 3H), 3.00(s, 6H), 4.32(q, 1H),7.30-7.99(m, 9H) ppm; IR(neat) 1660, 1595, 1400, 1280 cm⁻¹.

According to substantially the same procedure as that of Example 10,there were obtained the oxadiazole derivatives of the formula (XI) aslisted in Table 10.

                                      TABLE 10                                    __________________________________________________________________________    Example                                                                            Structure                      Physical Data                             __________________________________________________________________________    12                                                                                  ##STR74##                     NMR(CDCl.sub.3)δ3.00(s,6H),                                             4.13(s,2H),7.33-7.93 (m,9H) ppm;                                              IR(neat) 1660, 1600, 1400, 1280                                               cm.sup.-1                                 13                                                                                  ##STR75##                     mp 65-67° C.                       14                                                                                  ##STR76##                     mp 60-61° C.                       15                                                                                  ##STR77##                     mp 109.5-110.5° C.                 16                                                                                  ##STR78##                     mp 128.0-128.5° C.                 17                                                                                  ##STR79##                     mp 114.0-114.5° C.                 18                                                                                  ##STR80##                     mp 116.5-117.0° C.                 19                                                                                  ##STR81##                     NMR(CDCl.sub.3)δ1.72(d,3H),                                             1.94(m,4H),3.41(m,4H), 4.34(q,1H),7.30                                        -8.11 (m,9H) ppm; IR(neat)1660,1595,                                          1410,1285 cm.sup.-1                       20                                                                                  ##STR82##                     NMR(CDCl.sub.3)δ1.71(d,3H),                                             2.93(s,3H),4.26(q,1H), 4.57(s,2H),7.05                                        -7.60 (m,13H)ppm; IR(neat)1595,1485,14                                        55, 1410,1265 cm.sup.-1                   __________________________________________________________________________

EXAMPLE 21 ##STR83##

A mixture of 2-(2-fluoro-4-biphenylyl)propionic acid (5.00 g, 20.5 mmol)and thionyl chloride (10 ml) in benzene (50 ml) was stirred under refluxfor 4 hr and the solution was evaporated under reduced pressure toafford the acid chloride. After the acid chloride was dissolved inacetone (15 ml), the solution was added to cyanamide (1.44 g, 30.8 mmol)in 2N-NaOH (16 ml) by portions at 0°-5° C. The mixture was controlledabove pH 10 by 2N-NaOH during addition. After the addition, the mixturewas stirred at room temperature for 15 hr, then diluted with water,acidified with 1N-HCl to pH 6 and extracted with ether. The water phasewas acidified with 1N-HCl to pH 3 and then extracted with chloroform.The chloroform extracts were washed with saturated NaCl aq., dried withmagnesium sulfate, then evaporated under reduced pressure to a residue,which was chlomatographed to affordN-(2-(2-fluoro-4-biphenylyl)propionyl)cyanamide. To hydroxylaminehydrochloride (2.20 g, 30.4 mmol) in pyridine (5 ml) was addedN-(2-(2-fluoro-4-biphenylyl)propionyl)cyanamide in ethanol (15 ml) byportion under cooling for 15 minute and the mixture was stirred at roomtemperature for 1 hr, then standed at room temperature overnight. To thereaction mixture was added 2N-NaOH (40 ml) to afford the precipitates.The precipitates were collected, washed with water, dried andrecrystallized with ethyl acetate to afford3-amino-5-(1-(2-fluoro-4-biphenylyl)ethyl)-1,2,4-oxadiazole (3.00 g, 52%yield): mp 174.5°-175.0° C.

According to substantially the same procedure as that of Example 21,there were obtained the oxadiazole derivatives of the formula (XIV) aslisted in Table 11.

                                      TABLE 11                                    __________________________________________________________________________    Example                                                                            Structure                  Physical Data                                 __________________________________________________________________________    22                                                                                  ##STR84##                 mp 122.0-123.0° C.                     23                                                                                  ##STR85##                 mp 173.0-174.0° C.                     __________________________________________________________________________

EXAMPLE 24 ##STR86##

To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (300 mg, 1.01mmol) in tetrahydrofuran (15 ml) was added benzoyl chloride (145 mg,1.03 mmol) and triethylamine (101 mg, 1.00 mmol) and the mixture wasstirred at room temperature overnight. After reaction, the reactionmixture was filterated and evaporated under reduced pressure to aresidue, which was chromatographed to afford2-benzamido-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (279 mg, 69%yield): mp 147°-147.5° C.

According to substantially the same procedure as that of Example 24,there were obtained the azole derivatives of the formula (XVII) aslisted in Table 12.

                                      TABLE 12                                    __________________________________________________________________________    Example                                                                            Structure                       Physical Data                            __________________________________________________________________________    25                                                                                  ##STR87##                      mp 126.5-128.0° C.                26                                                                                  ##STR88##                      mp 159.0-160.0° C.                27                                                                                  ##STR89##                      mp 143.0-143.5° C.                28                                                                                  ##STR90##                      mp 162.5-163.5° C.                29                                                                                  ##STR91##                      NMR(CDCl.sub.3)δ1.67(d,3H),                                             3.09(t,2H),3.77(s,3H), 3.89(t,2H),4.2                                         1(q,1H), 6.65(s,1H),7.05-7.56 (m,8H)                                          ppm; IR(neat)1660,1485 1430,1285,1115                                         ,755, 695 cm.sup.-1                      __________________________________________________________________________

EXAMPLE 30 ##STR92##

To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (5.00 g, 1.68mmol) in tetrahydrofuran (150 ml) was added ethyl chloroformate (1.82 g,16.8 mmol) and triethylamine (1.70 g, 16.8 mmol) and the mixture wasstirred under reflux for 2 hr. After cooling, the reaction mixture wasdiluted with water, then extracted with ethyl acetate. The extracts werewashed with 1N-HCl and water, dried, then evaporated under reducedpressure to a residue, which was chromatographed to afford2-ethoxycarbonylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (3.954g, 64% yield): NMR(CDCl₃)δ 1.31(t, 3H), 1.60(t, 3H), 4.25(m, 3H),6.58(s, 1H), 6.95-7.58(m, 8H) ppm; IR(nujol) 3280, 1720, 1290, 1230,1080 cm⁻¹.

According to substantially the same procedure as that of Example 30,there were obtained the azole derivatives of the formula (XVII) aslisted in Table 13.

                                      TABLE 13                                    __________________________________________________________________________    Example                                                                            Structure                        Physical Data                           __________________________________________________________________________    31                                                                                  ##STR93##                       NMR(CDCl.sub.3)δ1.62(d,3H),                                             4.20(q,1H),4.85(s,2H), 6.60(s,1H),6.                                          90-7.58 (m,8H),9.12(m,1H)ppm                                                  IR(nujol)1750,1560, 1380,1280                                                 cm.sup.-1                               32                                                                                  ##STR94##                       mp. 104.0-105.0° C.              33                                                                                  ##STR95##                       mp 93.5-94.5° C.                 34                                                                                  ##STR96##                       NMR(CDCl.sub.3)δ1.25(t,3H),                                             1.71(d,3H),4.26(q,3H), 5.98(s,1H),                                            6.94-7.58(m,8H)ppm; IR(neat)                                                  1810,1775, 1620,1240,1100                                                     cm.sup.-1                               35                                                                                  ##STR97##                       mp 136.0-136.5° C.               36                                                                                  ##STR98##                       NMR(CDCl.sub.3)δ1.41(t,3H),                                             1.68(d,3H),3.68(s,3H), 4.24(q,1H),4.                                          43(q,2H), 6.73(s,1H),7.07-7.55                                                (m,8H)ppm; IR(neat)1745,1670,                                                 1520,1490,1440,1420 1285,1240,1100,1                                          070, 760 cm.sup.-1                      37                                                                                  ##STR99##                       mp 123.5-125.0° C.               38                                                                                  ##STR100##                      NMR(CDCl.sub.3)δ1.22(t,3H),                                             1.58(d,3H),3.40(s,3H), 4.15(q,2H),4.                                          98(q,1H), 7.02-7.55(m,9H)ppm;                                                 IR(neat)1750,1700, 1600,1420,1220,                                            1140 cm.sup.-1                          __________________________________________________________________________

EXAMPLE 39 ##STR101##

To a mixture of 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (500mg, 1.68 mmol) and triethylamine (340 mg, 3.36 mmol) in tetrahydrofuranwas added methanesulfonyl chloride (385 mg, 3.36 mmol) by portion andthe mixture was stirred at room temperature overnight. The reactionmixture was diluted with water, extracted with ethyl acetate andevaporated under reduced pressure to a residue, which waschromatographed and then recrystallized to afford2-methanesulfonylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (447mg, 71% yield): mp 127.5°-129.0° C.

According to substantially the same procedure as that of Example 39,there were obtained the azole derivatives of the formula (XVII) aslisted in Table 14. PG,51

                                      TABLE 14                                    __________________________________________________________________________    Example                                                                            Structure                        Physical Data                           __________________________________________________________________________    40                                                                                  ##STR102##                      mp 111.0-114.0° C.               41                                                                                  ##STR103##                      mp 163.0-164.0° C.               42                                                                                  ##STR104##                      mp 170.5-172.0° C.               43                                                                                  ##STR105##                      NMR(CDCl.sub.3)δ1.65(d, 3H),                                            4.12(q, 1H), 4.32(s, 2H), 5.45(s,                                             1H), 7.06-7.56 (m,                                                            8H)ppm; IR(neat)1600, 1560, 1410,                                             1350 cm.sup.-1                          44                                                                                  ##STR106##                      NMR(CDCl.sub.3)δ1.67(d, 3H),                                            3.32(s, 3H), 4.18(q, 1H), 5.99(s,                                             1H), 6.99-7.74 (m,                                                            8H)ppm; IR(neat)1590, 1480, 1420,                                             1365, 1175, 1070, 985, 835, 750,                                              725 cm.sup.-1                           45                                                                                  ##STR107##                      NMR(CDCl.sub.3)δ1.59(d, 3H),                                            3.27(s, 3H), 3.41(s, 3H), 4.01(q,                                             1H), 7.05-7.55 (m,                                                            9H)ppm; IR(neat)1590, 1360, 1160,                                             980, 880, 850 cm.sup.-1                 46                                                                                  ##STR108##                      NMR(CDCl.sub.3)δ1.64(d, 3H),                                            2.97(s, 3H), 4.06(q, 1H), 4.73(q,                                             2H), 7.09-7.56 (m, 14H)ppm;                                                   IR(neat)1590, 1360, 1170, 970, 850                                            cm.sup.-1                               __________________________________________________________________________

EXAMPLE 47 ##STR109##

To 2-phenylacetamido-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (1.00 g,2.51 mmol) in tetrahydrofuran (20 ml) was added lithium aluminu hydride(150 mg) by portion, then the mixture was refluxed for 2 hr. Aftercooling, the reaction mixture was filterated and evaporated underreduced pressure to a residue. The residue was extracted with chloroformand the extracts were washed with water, dried, then evaporated underreduced pressure to a residue, which chromatographed and recrystallizedto afford 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-phenethylaminothiazole(504 mg, 50% yield): mp 74.5°-75.5° C.

EXAMPLE 48 ##STR110##

To 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylaminothiazole (415 mg,1.33 mmol) in benzene (6 ml) was added methyl iodide (370 mg, 2.61mmol), tetra-n-butyl ammonium hydrogene sulfate (435 mg, 1.33 mmol) and50% NaOH aq. (3 ml), then the mixture was stirred at room temperatureovernight. The reaction mixture was diluted with water, then acidifiedwith 2N-HCl to pH 6 and the aqueous solution was extracted with benzene.The extracts were washed with water, dried and then evaporated underreduced pressure to a residue, which chromatographed to afford4-(1-(2-fluoro-4-biphenylyl)ethyl-2-dimethylaminothiazole (369 mg, 85%yield): NMR(CDCl₃)δ 1.62(d, 3H), 3.06(s, 6H), 4.09(q, 1H), 6.06(s, 1H),7.02-7.63(m, 8H) ppm; IR(neat) 2950, 1620, 1550, 1420, 1340 cm⁻¹.

According to substantially the same procedure as that of Example 48,there were obtained the azole derivatives of the formula (XLV) as listedin Table 15.

                                      TABLE 15                                    __________________________________________________________________________    Example                                                                            Structure                     Physical Data                              __________________________________________________________________________    49                                                                                  ##STR111##                   mp 87.0-88.0° C.                    50                                                                                  ##STR112##                   NMR(CDCl.sub.3)δ0.97(t, 3H),                                            1.60(d, 3H), 1.60-1.69 (m, 2H),                                               3.10-3.18(m, 2H), 4.06(q, 1H),                                                5.12-5.30(m, 1H), 6.15 (s, 1H),                                               7.02-7.54 (m, 8H)ppm; IR(neat)3200,                                           1620, 1340, 1260 cm.sup.-1                 51                                                                                  ##STR113##                   NMR(CDCl.sub.3)δ1.26(d, 6H),                                            1.60(d, 3H), 3.45-3.62 (m, 1H),                                               4.05(q, 1H), 5.50-5.80(m, 1H), 6.12(s,                                        1H), 7.03-7.54 (m, 8H)ppm; IR(nujol)330                                       0, 1630, 1380, 1270 cm.sup.-1              52                                                                                  ##STR114##                   NMR(CDCl.sub.3)δ0.94(t, 3H),                                            1.33-1.47(m, 2H), 1.61(d, 3H),                                                1.56-1.66 (m, 2H), 3.16-3.21 (m, 2H),                                         4.06(q, 1H), 5.30-5.52(m, 1H), 6.15                                           (s, 1H), 7.03-7.54(m, 8H) ppm;                                                IR(nujol)3400, 1600, 1380, 1340, 1270                                         cm.sup.-1                                  53                                                                                  ##STR115##                   mp 102.5-103.5° C.                  54                                                                                  ##STR116##                   NMR(CDCl.sub.3)δ1.56(d, 3H),                                            3.77(s, 6H), 4.02(s, 4H), 4.03(q, 1H),                                        4.52(s, 1H), 7.15-7.60(m, 9H)ppm;                                             IR(neat)2970, 1610, 1430, 1210                                                cm.sup.-1                                  55                                                                                  ##STR117##                   mp 89.0-90.0° C.                    __________________________________________________________________________

EXAMPLE 56 ##STR118##

To 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylaminothiazole (200 mg,0.64 mmol) in methanol was added citric acid (60 mg, 0.64 mmol) inmethanol and the mixture was stirred at room temperature, thenevaporated under reduced pressure to a residue, which was recrystallizedto afford 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylamino-thiazolecitrate: mp 150°-151° C.

EXAMPLE 57 ##STR119##

A mixture of 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)oxazole (1.66 g,5.88 mmol) and ethyl orthoformate (20 ml) was refluxed for 5 hr and thereaction mixture was evaporated under reduced pressure to a residue. Tothe residue in ethanol (50 ml) was added sodium borohydride (0.27 g,7.14 mmol) under cooling, then the mixture was stirred at roomtemperature for 2 hr. After evaporation, the residue was extracted withethyl acetate and the extracts were washed with water, dried and thenevaporated under reduced pressure to a residue, which waschromatographed and recrystallized to afford4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylaminooxazole (0.66 g, 40%yield): mp 133.5°-135.0° C.

According to substantially the same procedure as that of Example 57,there was obtained the azole derivative of the formula (XXIV) as listedin Table 16.

                                      TABLE 16                                    __________________________________________________________________________    Example                                                                            Structure                 Physical Data                                  __________________________________________________________________________    58                                                                                  ##STR120##               mp 104.0-105.0° C.                      59                                                                                  ##STR121##               NMR(CDCl.sub.3)δ1.59(d, 3H), 2.85(d,                                    3H), 4.04(s, 4H), 4.05(q, 1H), 4.34(m,                                        1H), 4.63(s, 1H), 7.15-7.60 (m, 9H)ppm;                                       IR(neat)3300, 2980, 1620, 1420, 1215                                          cm.sup.-1                                      60                                                                                  ##STR122##               mp 135.5-136.5° C.                      61                                                                                  ##STR123##               NMR(CDCl.sub.3)δ1.65(d, 3H), 2.88(d,                                    3H), 4.03(s, 4H), 4.20(q, 1H), 4.33(m,                                        1H), 7.16-7.60(m, 9H)ppm; IR(neat)3330,                                       3000, 2900, 1610, 1460, 1220, 1180, 1090,                                     1080 cm.sup.-1                                 __________________________________________________________________________

EXAMPLE 62 ##STR124##

To 3-amino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (1.20 g, 4.09mmol) in toluene (10 ml) were added ethyleneglycol (0.80 g, 12.9 mmol)and p-toluenesulfonic acid monohydrate (0.025 g, 0.15 mmol). Afterreflux for 10 h, the mixture was cooled at room temperature andextracted with toluene. The extracts were washed with aqueous sodiumhydrogen carbonate and then water, dried with anhydrous sodium sulfate,and evaporated under reduced pressure to a residue, which waschromatographed to afford3-amino-5-(1-(3-(2-phenyl-1,3-dioxolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole(1.06 g, 77% yield) as crystalline material: mp 112.0°-113.5° C.

EXAMPLE 63 ##STR125##

To 3-amino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (0.60 g, 2.0mmol) in pyridine (10 ml) was added methoxyamine hydrochloride (0.224 g,2.7 mol). After reflux with stirring for 18 h, the mixture was pouredupon ice water, extracted with ethylacetate. The extracts were washedwith water, dried with anhydrous sodium sulfate, and evaporated underreduced pressure to a residue, which was chromatographed to afford3-amino-5-(1-(3-(α-methoxyiminobenzyl)phenyl)ethyl)-1,2,4-oxadiazole(0.678 g, quantitive yield) as oily substance: NMR(CDCl₃)δ 1.70 (d, 3H),3.97(s, 3H), 4.24(q, 1H), 4.48(broad singlet, 2H), 7.21-7.58(m, 9H) ppm;IR(neat) 3310, 1625, 1585, 1410, 1050 cm⁻¹.

EXAMPLE 64 ##STR126##

To 3-dimethylamino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (1.0 g,3.11 mmol) in ethanol (10 ml) were added hydroxylamine hydrochloride(0.25 g, 3.45 mmol) in water (2 ml) and sodium hydroxide (0.40 g, 9.5mmol) in water (2 ml). After reflux with stirring for 24 h, the mixturewas poured upon ice water and extracted with ethyl acetate. The ethylacetate extracts were washed with saturated NaCl aq. dried withanhydrous magnesium salfate, and evaporated under redused pressure to aresidue, which was chromatographed to afford3-dimethylamino-5-(1-(3-(α-hydroxyiminobenzyl)phenyl)ethyl)-1,2,4-oxadiazole(0.873 g, 84% yield) as oily substance: NMR(CDCl₃)δ 1.66(d)+1.77(d)(3H), 2.98(s, 6H), 4.20(m, 1H), 7.22-7.55(m, 9H) ppm; IR(neat)3700-3100, 1600, 1405 cm⁻¹.

According to substantially the same procedure as that of Example 64, thefollowing compounds were made.

                                      TABLE 17                                    __________________________________________________________________________    Example No.                                                                          Structure                    Physical Data                             __________________________________________________________________________    65                                                                                    ##STR127##                  NMR(CDCl.sub.3)δ1.66(d)+                                                1.69(d)(3H), 4.12(q)+ 4.26(q)(1H),                                            4.96(br) +5.08(br)(2H), 7.16-7.73(m,                                          9H), 10.20 (br, 1H)ppm; IR(neat)3325,                                         3200, 1630, 1460 cm.sup.-1                66                                                                                    ##STR128##                  NMR(CDCl.sub.3)δ1.62(d)+                                                1.72(d)(3H), 1.80˜2.03 (m, 4H),                                         3.23-3.53 (m, 4H), 4.26(m, 1H),                                               7.17-7.53(m, 9H), 9.62(br, 1H)ppm;                                            IR(neat)3250, 1600, 1490, 1415, 1200                                          cm.sup.-1                                 67                                                                                    ##STR129##                  NMR(CDCl.sub.3)δ2.95 (s)+2.97(s)                                        (6H), 4.02(s)+4.10(s) (2H),                                                   7.24˜7.52 (m, 9H), 9.68(br, 1H)                                         pm; IR(neat)3250, 1600, 1400                                                  cm.sup.-1                                 68                                                                                    ##STR130##                  mp 189.0˜190.0° C.           __________________________________________________________________________

EXAMPLE 69 ##STR131##

To sodium brohydride suspended (0.177 g, 4.7 mmol) in methanol (15 ml)under cooling with ice was slowly added dropwise3-dimethylamino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (1.45 g,4.5 mmol) in methanol (15 ml). After the mixture was stirred undercooling with ice for 1 h, 1N-HCl was added to the mixture, then themixture was adjusted at pH 6. The mixture was evaporated under reducedpressure to a residue, which was extracted with dichloromethane. Theextracts were washed with saturated NaCl aq., dried with anhydrousmagnesium sulfate, and evaporated under reduced pressure to a residue,which was chromatographed to afford3-dimethylamino-5-(1-(3-(α-hydroxybenzyl)phenyl)ethyl)-1,2,4-oxadiazole(1.50 g, 99% yield) as oily substance: NMR(CDCl₃)δ 1.45(d, 3H), 2.27(d,1H), 3.00(s, 6H), 4.20(q, 1H), 5.80(d, 1H), 7.20-7.45(m, 9H) ppm;IR(neat) 3375, 1600, 1405 cm⁻¹.

According to substantially the same procedure as that of Example 69, thefollowing compound was made.

                                      TABLE 18                                    __________________________________________________________________________    Example No.                                                                          Structure                  Physical Data                               __________________________________________________________________________    70                                                                                    ##STR132##                NMR(CDCl.sub.3)δ1.65(d, 3H),                                            2.96(br, 1H), 4.19(q, 1H), 4.50(br,                                           2H), 5.78(s, 1H), 7.15˜7.48(m,                                          9H)ppm; IR(neat)3500˜3200, 1630,                                        1590, 1420 cm.sup.-1                        __________________________________________________________________________

EXAMPLE 71 ##STR133##

To triethyl orthoformate (10 ml) was added3-amino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (0.30 g, 1.02mmol). After reflux for 4.5 h, the mixture was evaporated under reducedpressure to a residue, which was extracted with dichloromethane aftersaturated NaHCO₃ aq. was added. The extracts were washed with water,evaporated under reduced pressure to a residue, which waschromatographed to afford3-methylamino-5-(1-(3-(α-hydroxybenzyl)phenyl)ethyl)-1,2,4-oxadiazole(0.15 g, 48% yield) as oily substance: NMR(CDCl₃)δ 1.63(d, 3H), 2.82(d,4H), 4.18(q, 1H), 4.20(m, 1H), 5.73(d, 1H), 7.33-7.42(m, 9H) ppm:IR(neat) 3430, 3330, 3040, 1600, 1490, 1450, 1340, 1320, 1150 cm⁻¹.

EXAMPLE 72 ##STR134##

To triethyl orthoformate (6 ml) was added3-amino-5-(2-(2-fluoro-4-biphenylyl)ethyl)-1,2,4-oxadiazole (0.10 g,0.35 mmol). After the mixture was refluxed for 20 h, the mixture wasevaporated under reduced pressure to a residue, which was extracted withchloroform after water was added. The extracts were dried with anhydrouspotassium carbonate, and evaporated under reduced pressure to a residue,which was chromatographed to afford3-formylamino-5-(2-(2-fluoro-4-biphenylyl)ethyl)-1,2,4-oxadiazole (0.091g, 83% yield): NMR(CDCl₃)δ 1.86(d, 3H), 4.40(q, 1H), 7.00-7.65(m, 8H),9.06(broad, 2H) ppm; IR(nujol) 3275, 1740, 1580 cm⁻¹ ; mass m/e 311(M+).

EXAMPLE 73 ##STR135##

To the mixture of acetic acid (16 ml) and water (4 ml) was added3-methylamino-5-(1-(3-(2-phenyl-1,3-dioxolan-2-yl)phenyl)ethyl)-1,2,4-oxadiazole(0.643 g, 2.44 mmol). After the mixture was stirred at room temperatureovernight, the mixture was evaporated under reduced pressure to aresidue, which was extracted with dichloromethane after saturated NaHCO₃aq. was added. The extracts were washed with water, dried with anhydrousmagnesium sulfate, and evaporated under reduced pressure to a residue,which was chromatographed and recrystallized with ethyl acetate andn-hexane to afford3-methylamino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (0.446 g,59% yield) as crystalline material: mp 100°-101° C.

According to substantially the same procedure as that of Example 73, thefollowing compounds were made.

                                      TABLE 19                                    __________________________________________________________________________    Example No.                                                                          Structure                    Physical Data                             __________________________________________________________________________    74                                                                                    ##STR136##                  NMR(CDCl.sub.3) δ1.60(d,3H);                                            4.12(q,1H),4.40(m,2H), 4.86(s,1H),7.23                                        ˜7.85 (m,9H)ppm; IR(neat)3300,32                                        80,1650, 1620,1580,1480,1310                                                  cm.sup.-1                                 75                                                                                    ##STR137##                  NMR(CDCl.sub.3) δ1.63(d,3H),                                            2.83(d,3H),4.13(q,1H), 4.36(m,1H),4.70                                        (s,1H), 7.23˜7.88(m,9H)ppm;                                             IR(neat)3350,2980,1660, 1630,1420,1280                                         cm.sup.-1                                76                                                                                    ##STR138##                  NMR(CDCl.sub.3) δ1.63(d,3H),                                            2.90(s,6H),4.13(q,1H), 4.62(s,1H),7.23                                        ˜7.88 (m,9H)ppm; IR(neat)2950,16                                        60,1620, 1435,1280 cm.sup.-1              __________________________________________________________________________

EXAMPLE 77 ##STR139##

To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (500 mg, 1.68mmol) in chloroform (20 ml) was added methylisocyanate (0.10 mg, 1.75mmol) in chloroform (10 ml) under cooling with ice. After the mixturewas stirred, methylisocyanate (0.15 mmol, 2.63 mmol) was added to themixture, and then the mixture was stirred at room temperature overnight.The mixture was evaporated under reduced pressure to a residue, whichwas crystallized to affordN-methyl-N'-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazol-2-yl)urea (0.499g, 84% yield) as crystalline material: mp 208.5°-209.0° C.

According to substantially the same procedure as that of Example 77, thefollowing compounds were made.

                                      TABLE 20                                    __________________________________________________________________________    Example No.                                                                          Structure                        Physical Data                         __________________________________________________________________________    78                                                                                    ##STR140##                      NMR(CDCl.sub.3)                                                               δ1.65(d,3H), 2.87(d,3H),3.39                                            (s,3H), 4.13(q,1H),6.48(s,1H),                                                7.04˜7.56(m,8H),9.32                                                    (m,1H)ppm; IR(neat)3200,1670,                                                 1410,1320,1100 cm.sup.-1              79                                                                                    ##STR141##                      mp 161.5˜162.5° C.       80                                                                                    ##STR142##                      mp 87.0˜88.5° C.         81                                                                                    ##STR143##                      mp 113.0˜114.0°          __________________________________________________________________________                                            C.                                

EXAMPLE 82 ##STR144##

To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (0.50 g, 1.68mmol) in acetone (10 ml) were added phenylisothiocyanate (0.25 g, 1.85mmol) in acetone (5 ml) and sodium hydrogen carbonate (0.30 g). Afterthe mixture was refluxed for 10 h, phenyisothiocyanate (0.50 g, 3.70mmol) was added to the mixture, and then the mixture was refluxed for 2h. The mixture was evaporated under reduced pressure to a residue, whichwas chromatographed and recrystallized to affordN-phenyl-N'-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazol-2-yl)thiourea(0.115 g, 16% yield) as crystalline material: mp 176.5°-177.0° C.

According to substantially the same procedure as that of Example 82, thefollowing compounds were made.

                                      TABLE 21                                    __________________________________________________________________________    Example No.                                                                          Structure                        Physical Data                         __________________________________________________________________________    83                                                                                    ##STR145##                      NMR(CDCl.sub.3)1.65(d,3H),                                                    3.92(s,3H),4.15(q,1H), 6.60(s,1H),                                            6.95˜7.60 (m,13H)ppm;                                                   IR(neat)2930,1560, 1490,1300,1180,                                            1060 cm.sup.-1                        84                                                                                    ##STR146##                      mp 162.0˜163.0° C.       85                                                                                    ##STR147##                      mp 158.0˜159.0°          __________________________________________________________________________                                            C.                                

EXAMPLE 86 ##STR148##

To lithium diisopropylamide in tetrahydrofuran prepared withdiisopropylamine (0.187 g, 1.85 mmol) and n-butyllithium (1.9 mmol) wasadded 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (0.50 g, 1.68mmol) in tetrahydrofuran at -70° C. After the mixture was stirred for 20min, methylisothiocyanate (0.131 g, 1.8 mmol) in tetrahydrofuran wasadded to the mixture. After the mixture was stirred at room temperaturefor 3.5 h, the mixture was evaporated under reduced pressure to aresidue, which was extracted with chloroform. The extracts were washedwith water, dried over, and evaporated under reduced pressure to aresidue, which was chromatographed and recrystallized to affordN-methyl-N'-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazol-2-yl)thiourea(0.233 g, 35% yield) as crystalline material: mp 180.5°-181.0° C.

According to substantially the same procedure as that of Example 86, thefollowing compounds were made.

                                      TABLE 22                                    __________________________________________________________________________    Example No.                                                                          Structure                         Physical Data                        __________________________________________________________________________    87                                                                                    ##STR149##                       NMR(CDCl.sub.3)                                                               δ1.68(d,3H), 3.15(d,3H),3.9                                             0(s,3H), 4.17(q,1H),6.60(s,1H),                                               6.97˜7.6(m,8H),11.89                                                    (br,1H)ppm; IR(neat)3110,1560,                                                1500,1300,1045 cm.sup.-1             88                                                                                    ##STR150##                       NMR(CDCl.sub.3)                                                               δ1.66(d,3H), 0.80-2.20(m,1H                                             ),3.90 (s,3H),4.16(q,1H),                                                     6.65(s,1H),6.90-7.67 (m,8H),11.90                                             (m,1H), ppm; IR(neat)3150,1560,                                               1500,1335,1315,1075, 1040,760                                                 cm.sup.-1                            89                                                                                    ##STR151##                       mp 172.0-173.0° C.            90                                                                                    ##STR152##                       mp 167.0-178.0° C.            __________________________________________________________________________

EXAMPLE 91 ##STR153##

To N-benzoyl-N'-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazol-2-yl)thiourea(0.25 g, 0.561 mmol) in mixture of acetone (10 ml) and methanol (2.5 ml)was added potassium carbonate (0.05 g) in water (1 ml). After themixture was refluxed for 5 h, the mixture was extracted with ethylacetate. The extracts were washed with water, dried over, and evaporatedunder reduced pressure to residue, which was chromatographed andrecrystallized with mixture of chloroform and n-hexane to affordN-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazol-2-yl)thiourea (0.172 g, 82%yield) as crystalline material: 192.0°-194.0° C.

According to substantially the same procedure as that of Example 91, thefollowing compound was made.

                                      TABLE 23                                    __________________________________________________________________________    Example No.                                                                          Structure                 Physical Data                                __________________________________________________________________________    92                                                                                    ##STR154##               mp 150.0-151.0° C.                    __________________________________________________________________________

EXAMPLE 93 ##STR155##

To 2-ethoxalylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (0.50 g,1.29 mmol) in ethanol (10 ml) was added ammonia water (2 ml). After theaddition, the mixture was refluxed for 2 h, evaporated under reducedpressure to a residue, which was extracted with chloroform. The extractswere dried over and evaporated under reduced pressure to residue, whichwas chromatographed to afford2-oxamoylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (0.121 g, 26%yield) as crystalline material: mp 179.0°-180.0° C.

According to substantially the same procedure as that of Example 93, thefollowing compound was made.

                                      TABLE 24                                    __________________________________________________________________________    Example No.                                                                          Structure                   Physical Data                              __________________________________________________________________________    94                                                                                    ##STR156##                 mp 230.5° C. (decomposition)        __________________________________________________________________________

EXAMPLE 95 ##STR157##

To oxalylchloride (1.22 g, 9.61 mmol) in tetrahydrofuran (20 ml) wasadded dropwise 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylthiazole (1.00g, 3.20 mmol) in tetrahydrofuran (10 ml). After the addition, themixture was stirred for 1 h at room temperature, then to the mixture wasadded dropwise di-n-butylamine (4.14 g, 32.0 mmol) in pyridine (5 ml)under cooling. After the addition, the mixture was stirred for 1 h atroom temperature and extracted with ethyl acetate. The extracts werewashed with water, dried over and evaporated under reduced pressure to aresidue, which was chromatographed to affordN',N'-di-n-butyl-N-methyl-N-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole-2-yl)oxamide(142 mg, 9% yield) as oily substance: NMR(CDCl₃) δ 0.89(t, 3H), 0.97(t,3H), 1.23-1.45(m, 4H), 1.55-1.70 (m, 9H), 3.21(t, 2H), 3.45(t, 3H),3.63(s, 3H), 4.25(q, 1H), 6.70(s, 1H), 7.08-7.55(m, 8H)ppm; IR(neat)2950, 1740, 1640, 1480, 1430, 1290, 1100 cm⁻¹.

According to substantially the same procedure as that of Example 95, thefollowing compounds were made.

                                      TABLE 25                                    __________________________________________________________________________    Example No.                                                                          Structure                        Physical Data                         __________________________________________________________________________    96                                                                                    ##STR158##                      mp 143.5-144.0° C.             97                                                                                    ##STR159##                      NMR(CDCl.sub.3) δ1.59-1.75                                              (m,9H),3.35(t,2H), 3.63-3.67(m,5H)                                            , 4.24(q,1H),6.70 (s,1H),7.07-7.56                                             (m,8H)ppm; IR(neat)2940,1740,                                                1650,1480,1430,1280, 1260,1100                                                cm.sup.-1                             __________________________________________________________________________

EXAMPLE 98 ##STR160##

To2-(N-methyl-N-(3-chloropropionyl)amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole(0.50 g, 1.24 mmol) in methanol (20 ml) was added ammonia water (5 ml).The mixture was refluxed for 5 h, and then evaporated under reducedpressure to a residue, which was extracted with ethyl acetate. Theextracts were dried over and evaporated under reduced pressure to aresidue, which was chromatographed and recrystallized with mixture ofethyl acetate and n-hexane to afford2-(N-methyl-N-(3-aminopropionyl)amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole(0.15 g, 39% yield) as crystalline material: mp 114.0°-117.0° C.

EXAMPLE 99 ##STR161##

To 4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylaminothiazole (16.0 g,51.2 mmol) in dichloromethane (600 ml) were added1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (24.0 g,0.125 mol), N-hydroxybenztriazole (10.7 g, 69.9 mmol), and(+)-2-p-chlorophenyl-3-methylbutyric acid (13.5 g, 63.5 mmol) undercooling with ice. The mixture was stirred at room temperature overnight,then washed with water, dried over, and evaporated under reducedpressure to a residue, which was chromatographed to afford twodiastereomers (A & B) of2-(N-methyl-N-(2-p-chlorophenyl-3-methyl-1-oxobutyl)amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazoleas crystalline materials.

                  TABLE 26                                                        ______________________________________                                                                       Chemical                                       Diastereomers                                                                           Yield   [α].sub.D.sup.25° C. (in                                                      Purityub.3)                                                                          mp                                      ______________________________________                                        A         3.73 g  +52.4°                                                                              99.4%  100.5 ˜                                                                 101.5° C.                        B         3.99 g  +31.8°                                                                              99.4%  143.0 ˜                                                                 143.5° C.                        ______________________________________                                    

To compound A of two diastereomers (2.50 g, 4.93 mmol) in ethanol (850ml) was added sodium peroxide (1.92 g, 24.6 mmol). After the mixture wasstirred at 50° C. for 2 h, ammonia water was added to the mixture. Themixture was evaporated under reduced pressure to a residue, which wasextracted with chloroform. The extracts were dried over and evaporatedunder reduced pressure to a residue, which was chromatographed andrecrystallized to afford(+)-4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylaminothiazole (0.70 g,45% yield) as crystalline material: mp 147.0°-148.0° C.; [α]_(D) ²⁵° C.(in CHCl₃) +29.2°; 92.6% ee*.

According to substantially the same procedure as the above withoutrecrystallization, with compound B of two diastereomers (2.50 g, 4.93mmol) was made(-)-4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylaminothiazole (0.90 g,58% yield) as crystalline material: mp 143.5°-145.0° C.; [α]_(D) ²⁵° C.(in CHCl₃) -21.5°; 88.8% ee*.

EXAMPLE 100 ##STR162##

A mixture of (+)-1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (27.7 mg,0.1 mmol; [α]_(D) ²⁵° C. +180° (c=0.744, CHCl₃), N-methylthiourea (9 mg,0.1 mmol) and sodium bicarbonate (9.2 mg, 0.11 mmol) in methanol (1 ml)was stirred at room temperature for 28 hr and the mixture was dilutedwith NaCl aq., then extracted with ethyl acetate. The extracts weredried with magnesium sulfate and evaporated under reduced pressure to aresidue, which was chromatographed to afford(+)-2-methylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (21.9 mg,70% yield): [α]_(D) ²⁵° C. +10.7° (c=0.15, CHCl₃); 70% ee.

What is claimed is:
 1. A compound of the formula: ##STR163## wherein Ais the group of the formula:

    Ar.sup.1 --D--Ar.sup.2 --

wherein Ar¹ is phenyl or thienyl which may be optionally substitutedwith at least one of the same or different halogen; Ar² is phenylene orthienylene which may be optionally substituted with at least one of thesame or different halogen; D is a divalent radical selected from thegroup consisting of >C═N--OR⁴, where R⁴ is hydrogen or loweralkyl, >C═O, ##STR164## >CHOH, >NH and a single bond; or A is the groupof the formula: ##STR165## wherein R⁵ is lower alkoxy or phenyl whichmay optionally substituted with at least one of the same or differenthalogen; E is methine or nitrogen; F is vinylene or oxygen; or A is thegroup of the formula: ##STR166## wherein R⁶ is lower alkoxy; R⁷ is loweralkyl; R⁸ is benzoyl which may be optionally substituted with at leastone of the same or different halogen; B is thiazolediyl; R¹ is hydrogenor lower alkyl; R² is hydrogen, lower alkyl, phenyl-lower alkyl, or thegroup of the formula:

    R.sup.9 --G--

wherein R⁹ is hydrogen, lower alkyl, halo-lower alkyl, amino-loweralkyl, phenyl or phenyl-lower alkyl or the group of the formula:##STR167## wherein R¹⁰ is hydrogen or lower alkyl; R¹¹ is hydrogen,lower alkyl, lower alkenyl, lower cycloalkyl, phenyl-lower alkyl, phenylor aroyl, or the group of the formula: --NR¹⁰ R¹¹ which is pyrrolidinyl,piperidinyl or hexahydroazepinyl, or the group of the formula:

    R.sup.12 --O--

wherein R¹² is lower alkyl or polyhalo-lower alkyl; G is a divalentgroup selected from the group consisting of >C═O, >C═S, (>C═O)₂ and >SO₂radical; or the group of the formula: --NR¹ R² which is pyrrolidinyl,piperidinyl or hexahydroazepinyl; R³ is hydrogen or lower alkyl, or itsacid addition salts.
 2. A compound of claim 1 wherein A is a group ofthe formula: Ar¹ --D--Ar² --.
 3. A compound of claim 1 wherein A is agroup of the formula: Ar¹ --D--Ar² -- wherein Ar¹ is phenyl which may beoptionally substituted with at least one of the same or differenthalogen; Ar² is phenylene which may be optionally substituted with atleast one of the same or different halogen; D is carbonyl or singlebond; and R³ is lower alkyl.
 4. A compound of claim 3 wherein A is agroup of the formula: ##STR168## wherein X is a hydrogen or halogenatom, or the formula: ##STR169##
 5. A compound of claim 3 wherein A is agroup of the formula: ##STR170## wherein X is a hydrogen or halogenatom, or the formula: ##STR171## and R² is a hydrogen atom or a loweralkyl group.
 6. A pharmaceutical composition for treatment of autoimmunediseases, which comprises as active ingredient a pharmaceuticallyeffective amount of at least one compound and its pharmaceuticallyacceptable acid addition salts as claimed in claim 1, and at least onepharmaceutically acceptable inert carrier or diluent.
 7. A method fortreatment of autoimmune diseases, which comprises administering to aperson a pharmaceutically effective amount of at least one compound andits pharmaceutically acceptable acid addition salts as claimed in claim1.